Abstract 4069: Therapy-associated clonal hematopoiesis and risk of hematologic malignancy after primary cancer treatment

Abstract Clonal hematopoiesis (CH) is the age-related expansion of hematopoietic stem cells, driven by single nucleotide variants (SNVs) or insertions and deletions (indels) in driver genes (clonal hematopoiesis of indeterminate potential, CHIP) or large-scale mosaic chromosomal alterations (mCAs). Both CHIP and mCAs are associated with increased hematologic malignancy risk. Prior studies have suggested cancer therapies may select for CH clones with DNA damage response mutations (e.g., CHIP in TP53). While therapy-related CHIP is recognized, the contribution of cancer treatment to mCA prevalence and the relationship of treatment-induced mCAs to subsequent cancer risk remains poorly understood. We investigated how exposure to cancer therapy may promote the acquisition or expansion of mCAs and consequently increase susceptibility to subsequent hematologic malignancies.Using genomic data from UK Biobank participants, we detected CHIP and mCAs in individuals with (N=24,607) and without prior cancer (N=453,763), classified as likely cancer therapy-exposed (hereafter referred to as exposed) or unexposed. We identified 422 exposed individuals who subsequently developed a hematologic malignancy. Logistic regression models, adjusted for age, age2, sex, smoking status, and genetic similarity, were used to compare CH prevalence between exposed and unexposed groups, and between participants in the exposed group who did and did not develop hematologic malignancies.Autosomal mCAs were detected in 5.2% of therapy-exposed individuals compared to 3.0% of unexposed individuals (OR=1.2, 95% CI=[1.1-1.3], p=9.6×10-6). CHIP was also enriched among therapy-exposed participants (7.6% vs. 4.5%; OR=1.4, 95% CI=(1.3-1.5), p=3.4 ×10-40). 17.5% of therapy-exposed individuals who developed incident hematologic malignancies harbored mCAs, compared with 3.7% who did not develop a hematologic malignancy (OR=4.9, 95% CI=[3.8-6.4], p=1.9×10-32), with notable enrichment of mCAs highly associated with hematologic malignancies (e.g., chromosome 9 p-arm copy-neutral loss of heterozygosity (chr9pCNLOH), chr14qCNLOH, and chr13q Loss). CHIP was observed at a frequency of 18.0%, compared to 6.3% of those who did not progress (OR=2.9, 95% CI=[2.2-3.7], p=8.3×10-16).These findings demonstrate that cancer therapy is associated with increased frequency of detectable CHIP and autosomal mCAs, with enrichment of mutations commonly observed in hematologic malignancies. Importantly, these events were detectable prior to diagnoses of a therapy-related hematologic malignancy, highlighting their potential as early indicators of hematologic malignancy risk in cancer survivors. Identifying high risk autosomal mCAs in this population could inform precision risk stratification and guide targeted surveillance strategies for individuals at risk of subsequent therapy-related hematologic malignancies. Citation Format: Kara Marie Barnao, Rebecca Lynn Kelly, Weiyin Zhou, Irenaeus Chan, Yin Cao, Kelly L. Bolton, Mitchell J. Machiela. Therapy-associated clonal hematopoiesis and risk of hematologic malignancy after primary cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4069.